Where Does Some of the Ingested Sodium Chloride Hide without Exerting Osmotic Pressure?
Authors: Titze J., Bauer K., Schafflhuber M., Dietsch P., Lang R., Schwind K.H., Luft F.C., Eckhardt K.-U., Hilgers K.F
Journal: Journal of the American Society of Nephrology (2006)

In the beginning the abundance of the sea [LINE SEPARATOR] Led to profligacy [LINE SEPARATOR] The ascent through the brackish waters of the estuary [LINE SEPARATOR] To the salt-poor lakes and ponds [LINE SEPARATOR] Made immense demands [LINE SEPARATOR] Upon the glands [LINE SEPARATOR] Salt must be saved, water is free. [LINE SEPARATOR] (Maurice B. Strauss, Boston) Since the introduction of the brilliant concept of Claude Bernard that the body comprises two distinct compartments the “milieu interieur” and the “milieu exterieur,” the partitioning between the two had been a challenge to the investigators. As Homer W. Smith pointed out and as beautifully described by the above sonnet, the transition from the salty sea to dry land created an enormous challenge to sodium homeostasis because of the need to preserve the precious sodium ion. Which mechanisms underlie sodium homeostasis? The early studies got it approximately right—but as we know today only approximately, and the early investigators had cautiously pointed to the limitations of their findings (1): The paradigm was that sodium is restricted mainly to the extracellular fluid and potassium to the intracellular space. The disequilibrium across the cellular membrane is maintained by the Na+,K+ATPase. The constancy of the extracellular space is mainly, but not exclusively, the task of mineralocorticoid activity. Unlimited sodium retention is prevented by the “safety valve” of the escape phenomenon, i.e., the onset of natriuresis despite persistently high mineralocorticoid activity when a hypothetical limiting size of the extracellular space has been transgressed. Needless to say, the regulation of the intravascular and extracellular spaces is of considerable clinical importance, given the disturbances of whole body sodium in congestive heart failure, nephrotic and nephritic syndrome, renal failure, and others. We have learned in physics that theories that explain findings satisfactorily (like the Maxwell equations) may break down when one goes to more extreme conditions and increases the precision of the measurements. Similarly, the careful and laborious studies of Titze et al. (2–5) shatter some firmly held beliefs, i.e., that sodium is restricted to the extracellular space and that it is retained only with a commensurate amount of water to maintain isosmolality. Of course, there had been pointers to this in the past, but the precise measurements and data had to wait for the above investigations. The aforementioned study by Titze et al. (2) addressed the issue whether, under the influence of mineralocorticoids (deoxycorticosterone-acetate, DOCA), sodium and water are retained in isosmotic proportions, in other words 1 L water per 9 g NaCl; and, if not, where the sodium that had failed to retain water had gone. To this end the authors examined female Sprague-Dawley rats receiving tap water or 1% saline as drinking fluid. These were compared with female Sprague-Dawley rats that had received subcutaneous DOCA pellets and were also kept on tap water or 1% saline. The salient results of this 5-wk study are the following. Despite considerable retention of sodium (0.255 ± 0.022 on DOCA compared with 0.170 ± 0.010 mmol/g dry weight without DOCA), the retention of water was only moderate and less than what was calculated assuming that water was retained to maintain isosmolality (0.685 ± 0.119 ml water/g wet weight on DOCA compared with 0.648 ± 0.130 ml water/g wet weight without DOCA). The calculation showed that 4.75 mmol Na+ had been retained, which should have caused the retention of 32 ml water. But only 7.75 ml water were detected, leading to the conclusion that 75 to 80% of the retained sodium was retained in an osmotically inactive form. This finding leads to the obvious question: Where does the sodium go? Tissues were subjected to desiccation and ashing to measure their electrolyte composition. In muscle, substantial amounts of sodium were retained (0.220 ± 0.029 ml water/g dry weight on DOCA compared with 0.145 ± 0.021 mmol/g dry weight without DOCA). This was associated with loss of potassium, suggesting that an isosmotic neutral exchange of K+ for Na+ had taken place; in other words osmotically neutral Na+ retention had occurred and was balanced by K+ loss. Although past studies had documented that the skin could indeed store sodium in an osmotically inactive form, the contribution of skin storage, although significant, was not so spectacular; in contrast to what had been seen in muscle it was not balanced by a K+ loss. This implies that there must have been osmotically inactive Na+ storage by another mechanism, e.g., by binding to glycosaminoglycans (3). Are these findings in line with previous observations? Indeed, balance studies in humans had documented that administration of sodium chloride did not invariably lead to volume retention (6–8). Conversely, it had also been observed that sodium loss is not necessarily paralleled by volume loss (9). The imbalance between sodium retention and water retention, pointing to “hidden” sodium stores, is particularly pronounced in patients with cardiac edema (10). Retention of more sodium than accounted for by the increase in the extracellular space had also been shown in the DOCA-salt model of the dog (11), and an increase in muscle sodium had been reported in DOCA rats (12,13). Though many mechanistic details await clarification, the obvious question is whether the findings have clinical implications. The classic concept that the BP increase induced by a positive sodium balance is simply explained by hypervolemia and a delayed autoregulatory increase of peripheral vascular resistance (14,15) requires reassessment and inclusion of complementary mechanisms, because direct uptake of sodium by vascular smooth muscle cells might well have a volume-independent hypertensinogenic effect. This might be particularly relevant in patients with impaired or absent renal function, where the BP-raising effect of a positive sodium balance is particularly pronounced (16,17). Another relevant issue is the sodium retention in cardiac (10) and nephrotic edema (18), which again require reassessment in the light of the above findings. Finally, as pointed out by the authors, the quantitative algorithms considered for the treatment of dysnatremias (19) might require modification as well.